Key issues in cementless total knee replacement (TKR) include the establishment and maintenance of fixation of the components to the host skeleton. This proposal is concerned with (i) using locally delivered growth factors to enhance early fixation by bone ingrowth into a porous coating, (ii) initial characterization of a circulating activity that stimulates bone regeneration and (iii) the mechanical competence of growth factor- enhanced fixation over time. Although the proposed experiments are designed with TKR in mind the findings will be relevant to any situation in which bone healing occurs through intramembranous bone formation. In the upcoming grant cycle, we plan to determine if TGF-beta and BMP-2 act additively or synergistically, to determine if local growth factor- induced stimulation of bone regeneration leads to the release of circulating factors that could explain our observations of elevated bone regeneration at remote sites, to quantify the increase in the early and long-term strength of fixation of non weight bearing implants and the mechanical stability of weight bearing implants when these growth factors are used. The proposed hypotheses will be tested using two in vivo canine models and in vitro cell and tissue culture techniques. More than 265,000 knee replacement procedures are now performed annually in the U.S compared to a rate of 120,000 annually in 1990. There is considerable variation among manufacturers with some reporting nearly 50% of the tibial components being designed for cementless implantation, whereby the component becomes attached to the host skeleton by bone ingrowth into a porous surface. Although there has been a relative decrease in the proportion of cementless TKR implants overall in the last few years, the absolute numbers of this type of replacement component may actually be increasing. The hypothetical advantage of a bone ingrowth interface is that the tissue can remodel over time and avoid accumulation of fatigue damage as can occur with inert interfaces such as those provided by bone cement. Our first hypothesis examines interaction (synergy v. additive effects) between TGF-beta and BMP-2 for enhancement of bone regeneration. The second hypothesis tests if a circulating activity is present after growth factor-induced augmentation of bone regeneration. The third hypothesis is concerned with the short and intermediate-term mechanical competence of growth factor stimulated bone and the fourth hypothesis address a simple question: given that gaps are inevitably present at the interface in weight- bearing implants, can this bone ingrowth-inhibiting condition be overcome with the use of growth factors known to stimulate bone healing and does enhancement of bone regeneration lead to greater implant stability?